Hormone Resistant Prostate Cancer

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A slide presentation on Hormone resistant prostate cancer and its management

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Hormone Resistant Prostate Cancer

  1. 1. Chemotherapy in HRPC Department of Medical oncology
  2. 2. Definition <ul><li>Hormone resistant prostate cancer </li></ul><ul><ul><li>A rising PSA despite androgen ablation </li></ul></ul><ul><ul><li>Manifests </li></ul></ul><ul><ul><ul><li>Rising PSA </li></ul></ul></ul><ul><ul><ul><li>Symotomatic Progression </li></ul></ul></ul><ul><ul><ul><li>Radiological evidence of progression despite the serum testosterone been at castrate levels </li></ul></ul></ul><ul><ul><li>BUT </li></ul></ul>
  3. 3. Defn contd <ul><li>Trials defined (similar) </li></ul><ul><ul><li>Men with advanced and progressive prostate cancer that had failed to respond to standard hormone therapy. Disease progression is observed despite castrate level of testosterone </li></ul></ul><ul><ul><li>The definition of disease progression </li></ul></ul><ul><ul><ul><li>appearance of new lesions </li></ul></ul></ul><ul><ul><ul><li>an increase in size (generally 25%) of existing lesions </li></ul></ul></ul><ul><ul><ul><li>an increase in pain </li></ul></ul></ul><ul><ul><ul><li>reduction in performance status </li></ul></ul></ul><ul><ul><ul><li>Decrease in weight </li></ul></ul></ul><ul><ul><ul><li>an increase in PSA levels </li></ul></ul></ul><ul><ul><li>No trial used a rising PSA level as the sole indicator of disease progression. </li></ul></ul>
  4. 4. EAU- defn <ul><li>Castrate serum levels of testosterone (testosterone <50 ng/dl or <1.7 nmol/l) </li></ul><ul><li> Three consecutive rises of PSA, 1 wk apart, resulting in two 50% increases over the nadir </li></ul><ul><li> Antiandrogen withdrawal for at least 4 wk for flutamide and for at least 6 wk for bicalutamide </li></ul><ul><li> PSA progression, despite consecutive hormonal manipulations </li></ul><ul><li> Progression of osseous lesions: progression or appearance of two or more lesions on bone scan or soft tissue lesions using Response Evaluation Criteria in Solid Tumours and with nodes >2 cm in diameter </li></ul>
  5. 5. Why treat? <ul><li>Morbidity </li></ul><ul><ul><li>QOL </li></ul></ul><ul><li>Mortality </li></ul><ul><ul><li>Incurable situation </li></ul></ul><ul><ul><li>Median life expectancy 12-18 months </li></ul></ul>Use of chemo for palliation Of symptoms and for survival benefit
  6. 6. Mitoxantrone The major toxicities were associated with mi- toxantrone include grade 3/4 neutropenia (7%), nausea and vomiting, alopecia (24%) and cardiotoxicity (66%).
  7. 7. Docetaxol TAX 327
  8. 8. Side effects
  9. 9. Other studies
  10. 10. Lesson learned? <ul><li>In view of the apparent lack of superior activity and greater toxicity by the addition of estramustine, docetaxel every 3 weeks plus low-dose prednisone can be considered as the current standard treatment </li></ul><ul><li>The optimal duration of docetaxel based chemotherapy for CRPC has not yet been established. </li></ul><ul><ul><li>Tax 327 10 cycles </li></ul></ul><ul><ul><li>SWOG 99-16 12 cycles. </li></ul></ul><ul><li>Standard practice is to treat patients with a fixed number of 10cycles of chemotherapy </li></ul>
  11. 11. Prognostic factors <ul><li>TAX 327 four independent risk factors predicted for not reaching a 30% PSA decline in 3-month PSA </li></ul><ul><ul><li>Significant baseline pain </li></ul></ul><ul><ul><li>Visceral metastases </li></ul></ul><ul><ul><li>anaemia (haemoglobin <13g/dl) </li></ul></ul><ul><ul><li>bone scan progression at baseline </li></ul></ul><ul><li>low-risk group 0−1 risk factors – Median OS 25.7 m </li></ul><ul><li>intermediate-risk group 2 risk factors – 18.7 m </li></ul><ul><li>high-risk group of patients 3−4 risk factors-12.8 months, </li></ul>
  12. 12. When to start therapy?
  13. 13. PSA DT
  14. 14. Response measurement <ul><li>PCWG 2 defined criteria of progression on the basis of changes in PSA, bone metastases, and measurable disease </li></ul><ul><ul><li>PSA progression has been defined as a 25% or greater increase and an absolute increase of 2ng/mL or more from the lowest documented PSA level,which is confirmed by a second value obtained 3 or more weeks later. </li></ul></ul><ul><ul><li>When the bone scan is the sole indicatorof progression- when at least two or more new lesions are seen on a bone scan compared with prior scans. </li></ul></ul><ul><ul><li>Measurable ds- RECIST </li></ul></ul><ul><li>Surrogate markers- 30% decline in PSA at 3 months and Post treatment PSA velocity </li></ul>
  15. 15. Addition in first line <ul><li>Endothelin receptor blockers </li></ul><ul><li>VEGF blockers </li></ul><ul><li>Calcitrol </li></ul><ul><li>Bisphosphonates </li></ul><ul><li>Vaccine immunotherapy </li></ul>
  16. 16. Endothelin recepetor <ul><li>Endothelin A – Atrasentan </li></ul><ul><ul><li>Phase 3 trial failed </li></ul></ul><ul><li>ZD4054 </li></ul>
  17. 18. <ul><li>VEGF </li></ul><ul><ul><li>CALGB 90401-Despite improvement in PFS, measurable disease response and post-therapy PSA decline, the addition of bevacizumab to docetaxel and prednisone did not improve OS in men with mCRPC, and was associated with greater morbidity and mortality </li></ul></ul><ul><ul><li>Afigerecpt (vegf trap) </li></ul></ul><ul><li>Calitriol </li></ul>
  18. 19. <ul><li>BUT </li></ul><ul><ul><li>Phase 3 trial was close by data safety monitoring commitee- high number of deaths </li></ul></ul>
  19. 20. <ul><li>Bisphosphonates </li></ul><ul><ul><li>Zolendronic </li></ul></ul><ul><ul><li>Riseadronate </li></ul></ul><ul><li>Vaccine immunotherapy </li></ul><ul><ul><li>Phase 3 trail was closed </li></ul></ul>Monotherapy of docetaxol remains std in first line
  20. 21. Denosumab <ul><li>Bone metastases from hormone-refractory (castration-resistant) prostate cancer (CRPC) are associated with RANKL-mediated osteoclast activation resulting in bone destruction and skeletal-related events (SRE) </li></ul><ul><li>Denosumab is a fully human monoclonal antibody against RANKL </li></ul><ul><li>120 mg subcut 4 weekly with ca and vit d supp </li></ul><ul><li>Denosumab demonstrated superiority over ZA in delaying or preventing SREs in patients with bone metastases from CRPC. </li></ul><ul><li>Adverse events were consistent in both treatment groups with those previously reported in advanced cancer populations. </li></ul>
  21. 22. Second line therapy <ul><li>Issues </li></ul><ul><ul><li>Elderly </li></ul></ul><ul><ul><li>Frail </li></ul></ul><ul><ul><li>Tolerability </li></ul></ul>
  22. 28. Metronomic chemotherapy <ul><li>HRPC who failed at least docetaxel-based chemotherapy were proposed metronomic cyclophosphamide-prednisolone regimen, and were prospectively registered </li></ul><ul><li>Metronomic cyclophosphamide prednisolone was safe, well tolerated, and demonstrated interesting clinical activity, yielding a </li></ul><ul><ul><li>prostate specific antigen decrease by ≥50% in 26% of patients </li></ul></ul><ul><ul><li>decrease by ≥30% in 48% of patients, but also favorable palliative effects on pain in 43% of patients. </li></ul></ul><ul><ul><li>The median progression-free survival was 6 months (95% CI: 4-8 months) and the median overall survival was 11 months (95% CI: 7-19 months). </li></ul></ul>
  23. 30. Conclusion <ul><li>Use of chemotherapy has increased survival in HRPC </li></ul><ul><li>The quest for newer and better agents in first and second line is ongiong </li></ul><ul><li>Use of metronomic in second line needs futher studies </li></ul>

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